17alpha, 21-alkoxy-methylenedioxy pregnenes and pregnadienes and process therefor



United States Patent 17a,2l-ALKOXY-METHYLENEDIOXY PREGNENES AND PREGNADIENES AND PROCESS THEREFQR Alberto Ercoii, Milan, and Rinaldo Garrli, Carate Brianza, Italy, assignors to Francesco Vismara S.p.A.,

Casatenovo (Como), Italy, a corporation of Italy No Drawing. Filed June 11, 1962, Ser. No. 201,296

Claims priority, application Italy June 24, 1961 9 Claims. (Cl. 260-23955) This invention relates to new 170L,2l-CYCllC orthoesters of steroids and particularly to 17a,21-(l-alkoxy)methylenedioxy derivatives of A -3-ketosteroids of the pregnane series. The invention further relates to a method of protecting the dihydroXy acetone side chain of a, A -3-ketopregnene compound by formation of a l7ot,2l-(l'-alkoxy) methylenedioxy derivative without the occurrence of undesirable side reactions.

It is known to prepare 16a,17a-substituted methylenedioxy derivatives from the corresponding l6a,l7oc,2l-trihydroXy steroids (J. Am. Chem. Soc. 82, 4625; 1960). The reaction occurs by treating such trihydroxylated steroid with methylor ethyl-orthoformate in the presence of a strong mineral acid, such as concentrated hydrochloric acid or perchloric acid, at a temperature from about to about 60 C.

The formation of a cyclic orthoester by the reaction of the vicinal cis-dihydroxy grouping of a 16a,l7oc,Z1-trihydroxy steroid cannot provide a satisfactory protection of the C-17-dihydroxy acetone side chain because only a portion of this chain is protected, that is the 17a-hydroxy group.

It is also known to prepare l7a,2l-ethoxymethylenedioxy derivatives from the corresponding 17a,21-dihy droxy steroids (Belgian Patent No. 594,221). The method of the prior art consists in reacting a 17a,21-dihydroxy steroid with ethyl orthoformate under inert atmosphere, or preferably under nitrogen atmosphere, in the presence of p.toluensulfonic acid at a temperature not higher than room temperature. Under such reaction conditions, the 17a,2l-dihydroxy steroid is converted to a 17a,2lethoxymethylenedioxy derivative, while certain other functional groups present in the steroid molecule are subjected to modifications.

For example, if the starting l7u,2l-dihydroxy steroid contains another hydroxy group at the 1l-position, this group is removed during the treatment with ethyl-orthoformate under the above operative conditions and a dehydration occurs between the 9- and ll-positions, thus obtaining a 17a,2l-ethoxymethylenedioxy derivative of a A -unsaturated steroid.

Moreover, if the starting 17a,2l-dioxy steroid contains a A -3-keto functional group, a concurrent enol-etherification occurs, modifying the A -3-ketogroup to a A diene-system. As result of the reaction with ethyl-orthoformate, a 3-ethoxy-A -pregnadiene-17a,21-ethoxyrnethylenedioxy is obtained. From these derivatives the A -3- ketogroup can be regenerated only by acid hydrolysis which treatment also regenerates the free C-17-dihydroxyacetone side chain.

l7a,2l-ethoxymethylenedioxy steroids which have become unsaturated at the 9-11 position and have lost the original A -3-ketogroup can no longer be employed as intermediates for the preparation, for instance, of 2-methylcorticoids, because the introduction of a methyl group at the 2-position of a l7a,2l-dihydroxy steroid, by a Claisen condensation, requires the deactivation of the C-17-dihydroxy-acetone side chain and the activation of the C-Z-position by the presence of a A -3-ketogroup.

Since most of the biologically active corticosteroids contain a A -3-ketogroup in addition to the dihydroxyacetone side chain and frequently an llB-hydroxy group,

, chloride.

the prior art cannot be said to teach a satisfactory method for protecting the dihydroXy-acetone side chain by treatment with ethyl-orthoformate, concurrent reactions occurring to modify the structure of the steroid molecule.

Such modifications are often irreversible and prevent using the resulting steroids for further reactions.

It is an object of the present invention to provide a method for reacting a A -3-keto corticosteroid with a lower alkyl orthoformate to form the protective 170;,21-

(1'-alkoxy)methylenedioxy grouping with little or no modification of other portions of the steroid molecule.

Another object of the invention is to provide new compounds which are useful as intermediates in the preparation of physiologically active A and A -3-keto steroids hlelrving the characteristic 17a,21-dihydroXy-acetone side c am.

Other objects of the invention will become evident from the following detailed explanation of our invention.

We have found that when a A -3-keto 170:,2l-dihYdI'0XY steroid is treated in the presence of an acid catalyst, with a lower alkyl orthoformate in the solution of a suitable organic solvent at a temperature from about 60 to about 130 C., there is obtained only the protection of the dihydroXy-acetone side chain of the steroid without modifying the A -3-keto functional group or, if present, the llfl-hydroxy group. Thus, we provide a new series of 17a,2l-alkoxymethylenedioxy steroids which may be represented by the following structural formulae:

1 2-0 00 CH-OR and where X represents a methylene, ,B-hydroxymethylene or ketonic group, Y is hydrogen or fluorine, R represents a lower alkyl group containing from 1 to 3 carbon atoms, inclusive and R is hydrogen, halogen, preferably chlorine or fluorine, or methyl.

The method of the present invention consists in treating the A -3-keto 17a,2l-dihydroxy steroid with an excess of a lower alkyl orthoformate, such as methyl, ethyl, propyl or isopropyl orthoformate, preferably with methyl or ethyl orthoformate, in the presence of an acid catalyst and in carrying out the reaction in solution in an appropriate organic solvent, at a temperature ranging from 60 C. to 130 C. Preferably the temperature is maintained during the reaction between C. and C. and for this purpose it is advisable to use a solvent having a boiling point higher than 60 C. Preferred solvents are dimethylformamide, benzene, hexane, isoctane or halogenated solvents, such as chloroform and carbon tetra- The acid catalysts of the reaction may be 3 selected from sulfonic aromatic acids, for instance, toluen-, benzen-, or naphthalenesulfonic acid, Lewis acids, such as SnCl or SbCl and salts of organic bases with mineral acids, particularly pyridine hydrochloride.

The reaction mixture, consisting of the starting l7oc,2ldiol, the lower alkyl orthoformate and the acid catalyst in solution in one of the above mentioned solvents, is heated at the above temperature for a period of from 30 minutes to 4 hours. We have found that the most satisfactory yields of l7a,2l-(l'-alkoxy)methylenedioxy steroids are realized by reacting the mixture in an apparatus equipped with a descending condenser. A portion of the solvent is distilled off and the remaining solution is neutralized by the addition of a few drops of pyridine. The 17a,2l-alkoxymethylenedioxy steroids are then obtained by concentration of the reaction mixture to dryness in vacuo followed by recrystallization of the product in the usual manner.

Under our operating conditions the reaction proceeds quantitatively in the sense of the formation of the 17a,Zlalkoxymethylenedioxy derivative. More specifically, enol-etherification of the A -3-keto group is avoided and enol-ethers do not form even in traces detectable by paper chromatography. Also dehydration at the 9(1l)-positlon does not occur when a llfl-hydroxy group is present.

his to be pointed out that the l7a,21-alkoxymethylenedioxy steroids of Formulae I and II can be obtained in two stereoisomeric forms owing to the new asymmetric carbon atom bridged with the two hydroxyl groups at the l7ocand 2l-positions. We have been able to isolate the two epimers and to identify them by the value of and the melting point. We have also found that the stereospecific synthesis of either of the two epimers depends essentially from the acid catalyst chosen for the reaction. In the presence of an aromatic sulfonic acid, such as p-toluenesulfonic acid, only the epimer having the lesser value of [04 is obtained, while in the presence of a salt of an organic base with a mineral acid, such as pyridine hydrochloride, there is obtained the epimer having the higher value of [(11 The l7a,2l-alkoxymethylenedioxy derivatives are stable under basic conditions but are easily hydrolyzable with a mineral acid in hot methanol to regenerate the free alcohols in high yield. As contrasted with other derivatives which have been employed for protecting the dihydroxy-acetone side chain, such as 17(20), 20(21)-bismethylenedioxy or 20- ethylcneketals, the new 17,2l-alkoxymethylenedioxy steroids of this invention contain at the 20-position a free carbonyl group which can thus be submitted to further transformations, for example reduction in an alkaline medium to give the corresponding 20-01 derivative. Hydrolysis with hydrochloric acid in boiling methanol will then provide l7u,20,2l-trihydroxy steroids.

Therefore the compounds of this invention are useful as intermediates for the practical synthesis of physiologically active steroids.

In particular, the compounds of Formula I in which the dihydroxy-acetone side chain is protected while the A -3-keto functional group is preserved are useful for the preparation of 2-methyl corticoids by reaction with diethyl oxalate and sodium methylate and treatment of the 2-enolate thus obtained with methyl iodide. By regenerating the dihydroxy-acetone side chain by treatment with mineral acids in hot methanol, a 2-methyl-A -3,20- diketo-l7a,21-dihydroxy steroid is obtained.

Furthermore the compounds of Formula I, where X is an hydroxymethylene group, and those of Formula II are useful for the preparation of esterified 11 ,B-hydroxy steroids. This is readily accomplished by treatment with an acylating agent according to known procedures, followed by hydrolysis of the l711,21-alkoxymethylenedioxy group with mineral acids as described above. The 11/3- acyloxy-17a,2\1-dihydroxy steroids are, in turn, useful for the preparation of the corresponding 115,21-dihydroxy steroids containing A -unsaturation, by first eliminating water at the l6,l7-position by treatment with phosphorus oxychloride or thionyl chloride and then hydrolyzing the llfi-acyloxy group with alkaline agents. This process would not be feasible with an unprotected llB-hydroxy group since concurrent dehydration would occur at the 9(ll)-position.

A further utility of the 170:,21-alkoxymethylenedioxy steroids of this invention lies in the fact they can be converted by hydrolysis under appropriate conditions to 1711- and 2l-monoformates. We have found that if a l7a,2l-alkoxymethylenedioxy steroid is treated with a diluted mineral acid, particularly hydrochloric acid, at room temperature or with an organic acid, particularly oxalic acid, with heating, there is obtained a mixture of l7a-monoformate and 21-monoformate which can be resolved by fractional crystallization. Thus the compounds of this invention make it possible to obtain the l7-monoformate of l7a,2l-dihydroxy steroids.

The new compounds of this invention as well as the process for their preparation, are illustrated by the following examples in which for the sake of convenience, the epimer with lesser value of [@1 is indicated as Form I and the epimer with higher value of [a] is indicated as Form II.

Example 1 To a mixture of 1.5 g. of A -pregnadiene-llfl,l7a,2ltriol-3,20-dione (prednisolone), 3 mg. of p.toluensulfonic acid and 600 cc. of anhydrous benzene contained in a flask equipped with a descending condenser there are added dropwise 1.2 cc. of methyl orthoformate (prepared as described by Pinner, Ber. 16, 1643; 1883). The mixture is distilled until the volume of the solution is reduced to 200 cc. The p-toluensulfonic acid is neutralized with a. few drops of pyridine and the solvent evaporated under vacuum. The residue taken up with a small amount of methanol yields 17a,21-methoxymethylenedioxy-l,4-pregnadiene-1lfl-ol-3,20-dione (Form I), M. Pt. 221-223 C.; [a] =|-97 (dioxan).

Under the same conditions, but employing as a catalyst pyridine hydrochloride instead of p.toluensulfonic acid, 17a,2l-methoxymethylenedioxy-1,4-pregnadiene llfi-ol- 3,20-dione (Form II) is obtained, M. Pt. l40-l42 C.; [u] (dioxan).

By substituting ethyl orthoformate (prepared as described by Pinner, Ber. 16, 1643; 1883) for methyl orthoformate, there is obtained 170:,2l-ethoxymethylenedioxy- 1,4-pregnadiene-l1/3-ol-3,20dione, either as Form I, M. Pt. 198200 C.; [a] =-|-85 (dioxan), or as Form II, M. Pt. -142" C.; [a] =+124 (dioxan).

The so obtained compounds can be hydrolyzed to 21- monoformates and l7u-monoformates by the following reaction sequence:

2 g. of l7a,2l-ethoxymethylenedioxy-1,4,pregnadiene- 1l,8-ol-3,20-dione (Form 1) are treated with 20 cc. of methanol and 3 cc. of oxalic acid 2 N. After 15 minutes heating at 40-50 C. followed by evaporation, the resulting residue is taken up with dilute methanol and a crystalline product is recovered which is A -pregnadienel1B, 17a,21-triol-3,20-dione-2l-formate, M. Pt. 240240 C.; [a] =+104 (dioxan).

By concentrating the mother liquor, l g. of A -pregnadiene-llfl,l7a,2l-triol-3,20-dione-l7-forrnate, M. Pt. 238-241 C.; [a] =+25 (dioxan), is isolated. After recrystallization from methanol, the melting point rises to 244-245 C.; [a] =-|20 (dioxan).

In a similar manner, starting from ll7a,2l-ethoxymethylenedioxy 1,4 pregnadiene 11B ol 3,20 dione (Form II), the same A -pregnadiene-1l/3,l7a,2l-tri0l- 3,20-dione-l7-formate, in corresponding yield, is obtained.

denser, is placed a solution of 2 g. of A -pregnene-17a,2l-

diol-3,20-dione (compound S), 5 mg. of p.toluensulfonic acid and 1.8 cc. of ethyl orthoformate in 2 cc. of dimethylformamide. The mixture is heated up to 110 C. and ethyl alcohol which has formed during the reaction is collected and distilled oif. After 3 hours heating, the p.toluensulfonic acid is neutralized with a few drops of pyridine and the solution is evaporated under vacuum. The residue taken up with a small amount of methanol and evaporated again yields l7ot,2l-ethoxymethylenedioxy-4-pregnene-3,ZO-dione (Form I) in an oily state;

Under the identical conditions described above, employing as catalyst pyridine hydrochloride instead of p.toluen sulfonic acid, 17a,21-ethoxymethylenedioxy-4-pregnene- 3,20-dione (Form II) is obtained, M. Pt. 147-149" C.; [a] 144.5 (dioxan).

Example 3 A mixture consisting of 2.5 g. of A -pregnene-11B,17a- 2l-triol-3,20-dione (hydrocortisone), 10 mg. of pyridine hydrochloride, 2 cc. of ethyl orthoformate and 2.5 cc. of

dimethylformamide is heated up to 115 C. for approxid mately 3 hours, then the solution is neutralized and evaporated under vacuum. Thus l7a,2l-ethoxymethylenedioxy-4-pregnene-1lfi-ol-3,20-dione (Form II) is obtained, M. Pt. 195l97 C.; [a] =+l70 (dioxan). By operating under the same conditions as described above, but employing as catalyst benzensulfonic acid instead of pyridine hydrochloride, 17a,21-ethoxymethylenedioXy-4- pregnene-l1/3,ol-3,20-dione (Form I) is obtained, M. Pt. 130-133 C.; [a] =+120 (dioxan).

The utility of the so obtained 17a,21-ethoxymethylenedioxy-4-pregnene-l1 8-ol-3,20-dione as an intermediate, is shown by the following example:

A suspension of 5 g. of 17,2l-ethoxymethylenedioxy- 4-pregnene-115-ol-3,20-dione in 100 cc. of t.butyl alcohol is treated with 2 g. of sodium methoxide and, then, with 2.8 cc. of diethyl oxalate. The resulting mixture is stirred for 6 hours and diluted with ether. The precipitate which forms is taken up with 250 cc. of acetone and re fluxed for 20 hours in the presence of 8 g. of potassium carbonate and 30 cc. of methyl iodide. After filtration, the mixture is concentrated under vacuum, diluted with water and extracted with ethyl acetate. The oily residue, obtained by evaporating the solvent, is dissolved in 200 cc. of absolute ethyl alcohol and reacted with 650 mg. of sodium methoxide.

After standing at room temperature for 4 hours, the mixture is treated with dilute hydrochloric acid, heated for 15 minutes on a water-bath, concentrated in vacuo and extracted with ethyl acetate.

By eliminating the solvent, a vitreous residue is obtained that is purified by chromatography, to obtain, in a crystalline state, 2a-methyl-4-pregnene-ll,8,17a,21-triol- 3,20-dione.

Example 4 2 g. of A -pregnene-l7a,21 diol-3,11,20-trione (corti- -SOne), 10 mg. of sulfosalicylic acid, 2 mg. of ethyl ortho- A mixture of 3 g. of 9a-fluoro-A -pregnadiene-11B, 17a,21-triol-3,20-dione, 10 mg. of p.toluensulfonio acid, 3 cc. of dimethylformamide and 3 cc. of ethyl orthoformate are heated to 110 C. After 4 hours heating, the solution is neutralized by addition of a few drops of pyridine and evaporated under vacuum. The residue taken 6 upwith methanol yields 9a-fluoro-l7u,2l-ethoxymethylenedioxy-1,4-pregnadiene-11B,ol-3,20-dione, Form I), M. Pt. 2l2214 C.; [a]|- (dioxan).

Example 6 2 g. of 9a-fluoro-A -pregnene-l1B,l7a,2l-triol-3,2O-dione are suspended in 800 cc. of carbon tetrachloride with 4 mg. of tin tetrachloride. The mixture while being distilled for a few minutes is treated with 1.5 cc. of methyl orthoformate and eyaporated to reduce the volume to 200 cc. After addition of a few drops of pyridine the solvent is evaporated in vacuo. The residue taken up with a small amount of methanol consists of 9ot-fll10IO-17cc21- methoxymethylenedioxy 4 pregnene 115,01 3,20

dione (Form I). Similarly, but employing pyridine hydrochloride as catalyst, 9oc-fluoro-17a,2l-methoxymethylenedioxy-4-pregnene-11fi-ol-3,20-dione (Form 11) is obtained.

In the same manner as above, there are prepared 60cchloro 17a-21 ethoxymethylenedioxy 4 pregnene- 1lfi-ol-3,20-dione (Form I), the corresponding Got-chloro- 1704,21 ethoxymethylenedioxy 4 pregnene 11,8 ol- 3,20-dione (Form II), 6a-fluoro-17a,2l-ethoxymethylenedioxy-4-pregnene-11fi-ol-3,20-dione and 6u-methyl-l7a,2lethoxymethylenedioxy 4 pregnene 11 8 ol 3,20 dione in both Form I and Form II.

Example 7 Example 8 2.5 g. of 6fl-chloro-A -pregnene-17a,21-diol-3,20-dione and 5 mg. of benzensulfonic acid are suspended in 2.5 cc. of dimethylformamide. The resulting mixture is treated with 2 cc. of methylorthoformate and following the procedure described in Example 2, 6/8-chloro-17a,2lmethoxymethylenedioxy-4-pregnene-3,20-dione (Form I) is obtained.

By substituting pyridine hydrochloride for benzensulfonic acid, Form II of this compound is obtained.

Similarly the following compounds are prepared:

6a fluoro l7oc,21 ethoxymethylenedioxy-4-pregnene- 3,20-dione (Form I);

6a fiuoro 17u,21 ethoxymethylenedioxy 4 pregnene-3,20-dione (Form 11);

65 methyl 17a,21-isopropoxymethylenedioxyi-pregnene-3,20-dione (Form I);

6B methyl 1711,21 isopropoxymethylenedioxy-4-pregnene-3,20-dione (Form II).

Example 9 By treating, as described in Example 1, a mixture of 3 g. of 60a methyl-9a-fluoro-A -pregnene-1lfl,l7a,2l-triol- 3,20-dione, 5 mg. of p.toluensulfonic acid and 1200 cc. of benzene with 4 cc. of ethylorthoformate, 6a-methyl-9afluorol7a,2 1 aethoxymethylenedioxy-4-pregnene-l 1 fi-ol-B 20-dione (Form I) is obtained.

Under the same conditions, but employing as catalyst pyridine hydrochloride, 6a methyl 9a fluoro-17a,2l-

ethoxymethylenedioxy 4 pregnene l1fi-ol-3,20-dione '(Form II) is prepared.

By substituting equivalent quantities of 6a,9a-difluoro- A -pregnene 11,8,17a,21 triol 3,20-dione, there is prepared 60,9oc difi110l0-17ot,21 ethoxymethylenedioxy 4- pregnene-11fl-ol-3,20-dione in both Form I and Form II.

Example 6a fluoro 17a,2l propoxymethylenedioxy 1,4 pregnadiene-1'1,9-ol-3,20-dione (Form I) and 6a fluoro 17o,21 propoxymethylenedioxy 1,4 pregdiene-l1B-ol-3,l0-dione (Form II);

60: methyl 170:,21 ethoxymethylenedioxy 1,4 pregnadiene-l1l3-ol-3,20-dione (Form 1) and 60a methyl 1711,21 ethoxyrnethylenedioxy 1,4-pregnadiene-llfi-ol-3,20-dione (Form II);

60: methyl 9oz fluoro-1711,2l-ethoxymethylenedioxy- 1,4-pregnadiene-11fi-ol-3,20-dione (Form 1) and 60a methyl 90c fluoro-17u,2l-ethoxymethylenedioxyl,4-pregnadiene-l1,B-ol-3,20-dione (Form II).

We claim: 1. A compound selected from the group consisting of a compound of the formula:

om-o\ 0 CHOIR.

and a compound of the formula:

om-o

0o CHOR wherein X is selected from the group consisting of methylene, ,B-hydroxymethylene and carbonyl groups, Y is selected from the group consisting of hydrogen and fluorine,

R is selected from the group consisting of lower alkyl groups of from 1 to 3 carbon atoms and R is selected from the group consisting of hydrogen, chlorine, fluorine and methyl.

2. 1704,21 ethoxymethylenedioxy 4 pregnene 3,20- dione.

3. 17or,21 ethoxymethylenedioxy-4-pregnene-3,11,20- trione.

4. 1701,2l-ethoxymethylenedioxy 4 pregnene-1 1,8-01- 3,20-dione.

5. 17rx,21-ethoxymethylenedioxy 1,4 pregnadiene- 11[3-ol-3,20-dione.

6. 1704,21-ethoxymethylenedioxy 9a fluoro-1,4-pregnadiene-l 1,6-01-3 ,20-dione.

7. 170:,21 ethoxymethylenedioxy 60c fluoro 4 pregnene-l l 6-01-3 ,ZO-dione.

8. 170.,21 ethoxymethylenedioxy 6a methyl 4- pregnene-l 15-01-3 ,ZO-dione.

9. A method of preparing a compound selected from the group consisting of a compound of the formula:

wherein X is selected from the group consisting of methylene, B-hydroxymethylene and carbonyl groups, Y is selected from the group consisting of hydrogen and fluorine, R is selected from the group consisting of lower alkyl of from 1 to 3 carbon atoms and R is selected from the group consisting of hydrogen, chlorine, fluorine and methyl which method comprises reacting the corresponding 17a,21-dihydroxy steroid with a lower alkyl orthoformate in the presence of an acid catalyst selected from the group consisting of sulfonic aromatic acids, Lewis acids and pyridine hydrochloride, in solution in an organic solvent selected from the group consisting of dimethylformamide, benzene, hexane, isoctane, chloroform and carbon tetrachloride at a temperature from 60 to C.

References Cited in the file of this patent Smith et al.: J.A.C.S., 82, 1960, pages 4625-4629.

Tanabe et al.: J.A.C.S., 83, February 5, 1961, pages 756 and 757. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA: 